单细胞RNA测序显示髓细胞S100A8/A9是压力过载后适应性肥厚向心力衰竭转变的一种新的调节因子。

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-07-28 eCollection Date: 2025-01-01 DOI:10.7150/thno.118369
Wei-Jia Yu, Wen-Xi Jiang, Shu-Jing Liu, Hui-Hua Li, Qiu-Yue Lin
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引用次数: 0

摘要

理由:免疫细胞浸润心脏在慢性压力过载后从适应性肥厚到心力衰竭(HF)的转变中起着至关重要的作用。然而,髓细胞中调节这一过程的关键因素仍然没有很好地定义。在此,我们研究了S100A8/A9在骨髓细胞中的功能作用。方法:采用横断主动脉缩窄法(TAC)致心肌肥厚、心衰模型1 ~ 4周。利用已发表的单细胞RNA测序数据集分析CD45+免疫细胞和S100A8/A9细胞来源的异质性。在S100A8基因敲除小鼠(KO)和骨髓嵌合小鼠(BM)以及体外共培养系统中验证了S100A8/A9对tac诱导的肥厚和HF的影响。结果:在HF患者和tac诱导的HF模型小鼠中,S100A8/A9水平显著升高。此外,在移植了S100A9-KO BM细胞的S100A9-KO小鼠和WT小鼠中,tac诱导的从适应性肥大到HF的转变明显减弱。机制上,tac刺激的中性粒细胞中S100A8/A9的上调通过激活p38 MAPK/JNK/AP-1通路诱导早期炎症反应和适应性肥大,导致IL-1β和趋化因子(CCL2和CCL6)的产生增加。这些趋化因子促进CCR2+巨噬细胞向受损心脏的浸润。因此,他们表现出S100A8/A9的上调,通过激活NF-κB/NLRP3、AKT/钙调磷酸酶A和TGF-β/Smad2信号通路,导致炎症加剧、心脏肥大和纤维化。此外,用S100A9抑制剂ABR-238901治疗WT小鼠可预防tac诱导的心肌肥厚相关功能障碍。结论:本研究结果在髓细胞和心肌细胞之间建立了一条与S100A8/A9相关的轴,该轴驱动压力过载诱导的从肥大到HF的转变,提示S100A8/A9是该疾病有希望的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Single-cell RNA sequencing reveals that myeloid S100A8/A9 is a novel regulator of the transition from adaptive hypertrophy to heart failure after pressure overload.

Rationale: Infiltration of immune cells into the heart plays a crucial role in the transition from adaptive hypertrophy to heart failure (HF) following chronic pressure overload. However, the key factors in myeloid cells that regulate this process are still not well defined. Here, we studied the functional role of S100A8/A9 in myeloid cells during this transition. Methods: Cardiac hypertrophy and HF models were induced by transverse aortic constriction (TAC) for 1 to 4 weeks. The heterogeneity of CD45+ immune cells and the cellular sources of S100A8/A9 were analyzed using published single-cell RNA sequencing datasets. The effects of S100A8/A9 on TAC-induced hypertrophy and HF were verified in S100A9 knockout (KO) and bone marrow (BM)-chimeric mice and in an in vitro coculture system. Results: S100A8/A9 levels were significantly increased in HF patients and in TAC-induced HF model mice. Moreover, the TAC-induced transition from adaptive hypertrophy to HF was significantly attenuated in S100A9-KO mice and WT mice transplanted with S100A9-KO BM cells. Mechanistically, TAC-stimulated upregulation of S100A8/A9 in neutrophils induced an early inflammatory response and adaptive hypertrophy through activation of the p38 MAPK/JNK/AP-1 pathway, leading to increased production of IL-1β and chemokines (CCL2 and CCL6). These chemokines promoted the infiltration of CCR2+ macrophages to the damaged heart. Therefore, they exhibited upregulation of S100A8/A9, which led to exacerbation of inflammation, cardiac hypertrophy and fibrosis via activation of the NF-κB/NLRP3, AKT/Calcineurin A and TGF-β/Smad2 signaling pathways. Additionally, treating WT mice with the S100A9 inhibitor ABR-238901 prevented TAC-induced cardiac hypertrophy-related dysfunction. Conclusion: The present findings establish an S100A8/A9-related axis between myeloid cells and cardiac cells that drives the pressure overload-induced transition from hypertrophy to HF, suggesting that S100A8/A9 is a promising therapeutic target for this disease.

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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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